Although the gene responsible for Huntington's disease (HD) has been localized to chromosome 4 (Gusella et al., Nature 306:234-238 (1983)), the pathogenesis of the illness remains obscure. One theory is that an "excitotoxic" process may play a role. This theory was originally based on the observation of similarities between kainic acid striatal excitotoxin lesions and the neuropathologic and neurochemical features of HD (Coyle and Schwarcz, Nature 263:244-246 (1976); McGeer and McGeer, Nature 263:512-519 (1976)). Schwarcz et al., Science 219:316-318 (1983) found that quinolinic acid striatal excitotoxic lesions are also similar to those of HD. Beal and co-workers found that this compound, and other agonists acting at the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors, could more accurately replicate the neurochemical and histologic features of HD (Beal et al., Nature 321:168-171 (1986) and Synopse 3:38-47 (1989)). The possibility that an excitotoxin acting at NMDA receptors is involved in HD has been strengthened by the finding of Young et al., Science 241:981-983 (1988) that NMDA receptors are profoundly depleted in HD. Moreover, this appears to be an early phenomenon in the course of the illness.
Although there have been many researchers investigating HD, little is known about its etiology and possible approaches to lessening or avoiding its effects.